1. Field of Invention
The invention relates to the use of adeno-associated viruses for decreasing the radiotherapy-induced or chemotherapy-induced resistance in patients who suffer from a cancer which is to be treated by radiotherapy or chemotherapy.
2. Description of Related Art
Along with the removal by surgery malignant diseases have been treated by radiotherapy and/or chemotherapy thus far. However, the occurrence of side-effects, in particular the development of resistances, limits the use of cytostatic agents. Because of these side-effects chemotherapeutic agents can only be used to a limited extent. Thus, the dosage of a chemotherapeutic agent can only be a dosage which the patient tolerates. However, in most cases such a dosage only achieves a minor curative effect.
Therefore, it is the object of the present invention to reduce or attenuate the problem of resistance induced by radiotherapy or chemotherapy so as to improve the survival rate of cancer patients after a radiotherapy or chemotherapy. In addition, it shall be possible to reduce the subsequent doses of a radiotherapy or chemotherapy. The responsiveness of tumor cells to radiotherapy or chemotherapy shall also be improved.
This object is achieved by the subject matters defined in the claims.
According to the invention the development of a radiotherapy-induced or chemotherapy-induced resistance in patients suffering from a cancer to be treated by radiotherapy or chemotherapy shall be reduced by using adeno-associated viruses.
It was found surprisingly that following a treatment with humans non-pathogenic adeno-associated viruses (AAV) the tumor cells respond in a better way to a subsequent chemotherapeutic or radiotherapeutic measure.
The AAV virus is a human parvovirus which requires co-infection with a helper virus for a productive infection to take place. AAV infects human in their infancy and is considered non-pathogenic, since no human disease could be correlated with the AAV infection (Adv. in Vir. Res., 1987, 32, 43-306).
According to the inventors"" insight, an AAV infection in combination with chemotherapeutic or radiotherapeutic measures increases the efficiency of a conventional therapy and reduces resistances which occur, so that a further therapy can be carried out in a more promising way than possible thus far. Any AAV viruses can be used according to the invention. The AAV-2 virus is used preferably.
In animal experiments carried out with immunodeficient nude mice into which small cell lung carcinoma cells were implanted subcutaneous, it could be shown that an AAV infection which was carried out at the same time as a chemotherapy resulted in a faster recession of the tumors. Relapses occurred after a short time in both group. However, in the AAV-infected chemotherapeutic group they responded better to another chemotherapy than those of the group only treated by means of chemotherapy. This shows that an AAV infection can reduce or even avoid the development of resistances.
The use of the AAV viruses according to the invention can be made before, at the same time with or after the chemotherapy or radiotherapy. However, it is carried out preferably after a first chemotherapeutic or radiotherapeutic treatment cycle.
In particular in the case of tumor kinds which per se show a poor response to a chemotherapy or radiotherapy it may be indicated to carry out the treatment before or together with the chemotherapy/radiotherapy to increase the efficiency of the therapy. By this the treatment doses can be lowered and therefore the side-effects can be reduced.
The radiotherapy or chemotherapy may be any radiotherapy or chemotherapy which is adapted to the cancer to be treated. Such therapies have been known for years and along with the removal of the tumor by surgery that represent the established method of curing cancer diseases or increasing the life expectancy of a patient by some time. Therefore, a person skilled in the art is perfectly familiar with the measures of a radiotherapy or chemotherapy.
The use of AAV viruses according to the invention can be applied to any cancer kinds, the best success being expectable in connection with colon cancers, pancreatic carcinomas and brain tumors (in particular glioblastomas). The small cell lung carcinoma (SCLC) can preferably be treated therewith.
The application according to the invention is made intravenously, by means of infusions, intratumorally, orally (also by means of inhalations) or cutaneously. In this connection, the virus is formulated in a suitable preparation adapted to the pathway of administration. For an intravenous (also as an infusion) and intratumoral administration it is preferred to provide the virus in a physiological common salt solution, Ringer""s solution or PBS solution (phosphate-buffered salt solution), for a cutaneous administration it is preferred to provide it in the form of an ointment, suspension or gel, and for oral administration it is preferred to provide it in the form of an aerosol spray.
Depending on the patient""s body weight the virus dose employed is 109-1010 AAV particles/kg body weight.
A pharmaceutical composition is also provided according to the invention which in addition to the chemotherapeutic agent (cytostatic agent) contains adeno-associated viruses, in particular AAV-2. All chemotherapeutic agents (cytostatic agents) common in tumor therapy thus far can be used separately or in combination as a chemotherapeutic agent, e.g. cisplatin, etoposide, methothrexate, doxorubicin, cyclophosphamide trofosfamide, busulfane, cytarabin, fluorouracil, mercaptopurins, vinblastinesulfate, vincristinesulfate, bleomycinsulfate or mitomycin. Thus, it is preferred for an intravenous (also by mean of infusion) and intratumoral administration to provide an injection solution, for a cutaneous administration to provide an ointment, for an oral administration to provide an aerosol spray. As a basis for the preparation of the infusion solution physiological common salt solution, Ringer""s solution or PBS each are suitable in pure form or as a mixture. The amount of AAV depends on the patient""s weight and is 109-1010 particles/kg body weight. In the pharmaceutical composition it is contained in an amount suitable for an average body weight of 70 kg. The accurate dosage of the pharmaceutical composition according to the invention is determined by a physician and depends on the patient""s sex and weight, severity of the disease, kind of administration and planned duration of administration. A composition according to the invention may also contain conventional auxiliary agents. The common auxiliary agents such as carriers, binders, blasting agents, lubricants, solvents, solubilizers, release accelerators, release decelerators, emulsifiers, stabilizers, colorants of the taste correctives may be used as auxiliary agents.